Enantiomers of O-desmethyl venlafaxine

ABSTRACT

This invention provides pharmaceutically active enantiomers of the venlafaxine metabolite O-Desmethyl venlafaxine, R(−)-4-[2-(Dimethylamino-1-(1-hydroxycyclo-hexyl)ethyl]phenol or R(−)1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]cyclo-hexanol, and S(+)-1-[2-(Dimethylamino)-1-(4-hydroxycyclohexyl)ethyl]cyclohexanol or S(+)-4-[2-(Dimethylamino)-1-(1-hydroxcyclohexyl)ethyl]phenol,or one one or more pharmaceutically acceptable salts or salt hydrates thereof, as well as pharmaceutical compositions utilizing these enantiomers and methods of using the enantiomers to treat, inhibit or control central nervous system disorders.

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/183,029, which was converted from U.S. patentapplication Ser. No. 09/333,594, filed Jun. 15, 1999, pursuant to apetition filed under 37 C.F.R. 1.53(c)(2)(i).

[0002] This invention provides enantiomers of O-desmethyl venlafaxine,(R/S) 4-[2-(Dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol, as wellas pharmaceutical compositions and uses thereof.

BACKGROUND OF THE INVENTION

[0003] Various patents and literature references describe the biologicalactivities of venlafaxine, and its salts and analogs. Venlafaxinehydrochloride tablets are marketed by Wyeth-Ayerst Laboratories underthe Effexor® trademark.

[0004] The absolute configuration of the (+) enantiomer of venlafaxinewas established as S by a single crystal X-ray analysis of thehydrobromide salt and the anomalous dispersion technique (Yardley etal., J. Med. Chem., 1990, 33; 2899).

[0005] (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanoland its metabolites1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]cyclohexanol and1-[1-(4-methoxyphenyl)-2-(methylamino)ethyl]cyclohexanol are disclosedand claimed in U.S. Pat. No. 4,535,186 (Husbands et al.). U.S. Pat. No.5,530,013 (Husbands et al.) claims the use of venlafaxine in theinducement of cognition enhancement. U.S. Pat. No. 5,506,270 (Upton etal.) claims venlafaxine's use in methods of treating hypothalamicamenorrhea in non-depressed women.

[0006] U.S. Pat. No. 5,788,986 (Dodman) and U.S. Pat. No. 5,554,383(Dodman) teaches and claims the use of serotonin reuptake inhibitors inmodifying the behavior of dogs.

SUMMARY OF THE INVENTION

[0007] This invention provides pharmaceutically active enantiomers ofthe venlafaxine metabolite O-Desmethyl venlafaxine,R(−)-4-[2-(Dimethylamino-1-(1-hydroxycyclo-hexyl)ethyl]phenol andS(+)-4-[2-(Dimethylamino)-1-(1-hydroxycyclo-hexyl)ethyl]-phenol, or apharmaceutically acceptable salt or salt hydrate thereof, having thestructures:

[0008] Particularly, this invention provides compositions of matter ofboth the R(−) enantiomer and S(+) enantiomer substantially free of eachother. Under a different system of nomenclatureS(+)-4-[2-(Dimethylamino)-1-(1-hydroxycyclohexyl)-ethyl]phenol may alsobe namedS(+)-1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)-ethyl]cyclohexanol.Similarly, R(−)-4-[2-(Dimethylamino-1-(1-hydroxycyclohexyl)-ethyl]phenolmay also be referred toR(−)1-[2-(dimethylamino)-1-(4-hydroxyphenyl)-ethyl]cyclohexanol. As usedherein, the designations (+) and (−) refer to the sign of rotation ofthe relevant free base.

[0009] These enantiomers and their pharmaceutically useful salts andhydrates are useful for the biological and pharmacological activitiesfor which venlafaxine and its salts are known in the art. Theseenantiomers may be used in treating or inhibiting central nervous systemdisorders, including depression, panic disorder, post-traumatic stressdisorder, late luteal phase dysphoric disorder (also known aspre-menstrual syndrome), attention deficit disorder, with and withouthyperactivity, generalized anxiety disorder, bulimia nervosa, Gilles dela Tourette Syndrome, Shy Drager Syndrome, vasomotor flushing, drug andalcohol addiction, sexual dsifunction (including premature ejaculation),borderline personality disorder, chronic fatique syndrome, fibromyalgia,urinary incontinence and others. These compounds are also useful in theinducement of cognition enhancement and in regimens for cessation ofsmoking or other tobacco uses.

[0010] Racemic1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]cyclohexanol can beproduced as described in Example 26 of U.S. Pat. No. 4,535,186 (Husbandset al.), which is incorporated herein by reference. It will beunderstood that the enantiomers may be separated from each other bystandard resolution techniques known in the art.

[0011] Alternatively, these R and S enantiomers may be obtained byO-demethylation of the separated enantiomers of venlafaxine using eitherboron tribromide or ethane thiol anion.

EXAMPLE NO. 1 1-[2-(Dimethylamino-1-(4-hydroxyphenyl)ethyl]cyclohexanolfumarate hydrate

[0012]

[0013] 1-[2-(Dimethylamino-1-(4-methoxyphenyl)ethyl]cyclohexanol-HCl(200 g=0.6372 mol) was dissolved in H₂O (500 mL). CH₂Cl₂ (350 mL) wasadded thereto and this mixture cooled to 10° C. At this temperature 2.5N NaOH (280 mL=0.7 mol) was added slowly over 1 hr. CH₂Cl₂ was separatedand the aqueous layer extracted with CH₂CL₂ (200 mL). Combined CH₂Cl₂extracts were dried (MgSO₄) filtered, and evaporated in vacuo to yield1-[2-(Dimethylamino-1-(4-methoxyphenyl)-ethyl]cyclohexanol free base(167.5 g=94.5%) as white solid, mp 77-79° C.

[0014] To a stirred solution of1-[2-(Dimethylamino-1-(4-methoxyphenyl)ethyl]-cyclohexanol-free base(13.87 g=50 mmols) in CH₂Cl₂ (300 mL) cooled to—40° C., under N₂ wasadded slowly BBr₃ (10 mL=105.5 mmols) over a period of 15 minutes. Thereaction mixture warmed to 0° C. where it stirred for 3 hrs. During thistime a gummy precipitate formed. Still at 0° C., 2.5N NaOH (200 mL) wasadded slowly over 1 hr, then allowed to warm to room temperature andstirred for 3 hrs. CH₂Cl₂ was removed by evaporation under reducedpressure leaving an aqueous layer having a pH=13-14. Aqueous layer wasextracted with EtOAc (3×100 mL) and its pH dropped to 9. Combined EtOAcextracts were dried (MgSO4), filtered, evaporated in vacuo to affordcrude phenol (9.3 g=71%) as a white solid, mp 208-213° C. (TLC) togetherwith some dehydrated product. This crude product was used in the nextstep without further purification.

[0015] Crude phenol (9.3 g=35.31 mmoles) and fumaric acid (4.91 g=42.37mmoles) were dissolved in a mixture of methanol/acetone (1:3) (195 mL),stirred at room temperature for 15 minutes. H₂O (0.8 mL=44.44 mmoles)was added to the clear light yellow solution. The whole was stirred atroom temperature for 3 hours. The resulting white precipitate wasfiltered, washed with acetone (30 mL) dried in air to yield 8.0 g=57%white solid, mp: 145-150° C.

EXAMPLE NO. 2R(−)-1-[2-(Dimethylamino-1-(4-methoxyphenyl)ethyl]cyclohexanol

[0016]

[0017] To a solution of yield1-[2-(Dimethylamino-1-(4-methoxyphenyl)ethyl]-cyclohexanol free base(100 g=0.36 mol) in EtOAc (750 mL) at room temp was added at once asolution of (+)-Di-para Toluoyl-D-tartaric acid-monohydrate (DT(−)T; 40g=0.0991 mol]. The whole was stirred at room temp for 1 hr. Theresulting precipitate was filtered off, washed with EtOAc (3×100 mL),dried overnight at 35° C. in a vacuum oven to provide crudeR(−)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)-ethyl]cyclohexanol DT(−)Tsalt (83 g=92.8%) as a white solid.

Recrystallization ofR(−)1-[2-(Dimethylamino-1-(4-methoxyphenyl)-ethyl]cyclo-hexanol, DT(−)TSalt

[0018] Crude DT(−)T salt (83 g) was dissolved in EtOAc (700 mL). Themixture was heated up to reflux. Methanol (75 mL) was added thereto toobtain a clear solution. The mixture was concentrated at atmosphericpressure to a volume of 400 mL (some solid started to precipitate). Themixture was cooled at 25° C. for 1 hr, then at 0° C. for another 2 hrsand filtered off to provide(−)1-[2-(Dimethylamino-1-(4-methoxy-phenyl)ethyl]cyclohexanol DT(−)Tsalt (63 g=77%). NOTE: Optical rotation of this salt in ethanol was+47.0°.

Isolation ofR(−)1-[2-(Dimethylamino-1-(4-methoxyphenyl)-ethyl]cyclohexanol Base

[0019] R(−)1-[2-(Dimethylamino-1-(4-methoxyphenyl)ethyl]cyclohexanolDT(−)T salt was slurried in a mixture of H₂O/CH₂Cl₂ (400 mL/400 mL). ThepH of this mixture was adjusted to 13 by adding 25% NaOH solution (120mL). The layers were separated, aqueous layer was extracted with CH₂Cl₂(1×200 mL). Combined CH₂Cl₂ layers were washed with H₂O (2×200 mL)saturated NaCl solution (1×200 mL), dried (MgSO₄) and evaporated atatmospheric pressure to a volume of 100 mL. Hexane (300 mL) was addedthereto and solution became hazy. After charcoal treatment (1 teaspoon),the filtrate was concentrated at atmospheric pressure to a volume of 250mL and allowed to cool. The resulting white precipitate was collected byfiltration, washed well with hexane (2×100 mL), dried in a vacuum ovenovernight to provideR(−)1-[2-(Dimethylamino-l-(4-methoxyphenyl)ethyl]cyclohexanol-base (28.5g). Recrystallization from CH₂/Cl₂/hexane (50 mL/200 mL) gaveanalytically pureR(−)1-[2-(Dimethylamino-1-(4-methoxyphenyl)ethyl]cyclohexanol base (23.5g=23.5%) Rotation=−31.08° (in ethanol). Anal. Calcd: C, 73.60; H, 9.81;N, 5.05 Found: C, 73.75, H, 9.73; N, 4.83.

EXAMPLE NO. 3R(−)-1-[2-(Dimethylamino-1-(4-hydroxyphenyl)ethyl]cyclohexanol fumaratehydrate salt

[0020]

[0021] To a cooled (−40° C.) stirred solution ofR(−)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol (13.87g=50 mmol) in CH₂Cl₂ (500 mL) under nitrogen was added slowly BBr₃ (10mL=105.5 mmols) over a period of 15 min. The reaction mixture warmed to0° C. where it stirred for 3 h. During this time a gummy precipitateformed. Still at 0° C., 2.5 N NaOH solution (200 mL) was added slowlyover 1 hr. The reaction mixture was allowed to warm to room temp andstirred overnight. Methylenechloride was removed, leaving an aqueouslayer having a pH—13-14. Aqeuous layer was extracted with EtOAc (3×100mL) and its pH dropped in 9. Combined EtOAc extracts were washed withbrine, dried (MgSO₄) and evaporated in vacuo to give crude phenol (6.5g—49.4%) as white solid. The crude phenol (6.5 g=24.68 mmols) andfumaric acid (1.2 eq; 3.3 g=29.61 mmols) were dissolved in a mixture ofmethanol/acetone (1:3) (135 mL) and stirred at room temp for 15 min.After this time H₂O (0.6 mL) was added to the clear light yellow coloredsolution. Precipitation was seen immediately. The suspension was stirredat room temp for 3 h. The resulting white precipitate was collected byfiltration, washed well with acetone (1×35 mL) and dried to providetitle compound (6.6 g=67.3%, mp 150-155° C. This was recrystallized fromMeOH/Acetone/H₂O (40 mL: 126 mL: 0.3 mL) to give 3.7 g (37.7%) ofanalytically pureR(−)-4-[2-(Dimethylamino)-1-(1-hydroxycyclo-hexyl)ethyl]phenol fumaratehydrate salt. Rotation: +6.60° (in methanol) for the fumarate hydrate,−15.58° (in methanol) for the free base. Anal. Calcd: C, 60.43; H, 7.86;N, 3.52. Found: C, 60.16; H, 7.64; N, 3.36.

EXAMPLE NO. 4R(−)-4-[2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol fumaratehydrate salt

[0022]

[0023] Under gentle N₂ stream 60% NaH (35 mmols=1.4 g) was washed withhexane, collected by filtration and transferred into a 250 mL 3 neckflask. DMF (20 mL) was added into the flask to cover the sodium hydrideand the suspension cooled to 10° C. Under stirring a solution of ethanethiol (32.40 mmols=2.075 g=2.47 mL) in DMF (5 mL) was added dropwiseover 40 min. During the addition of the ethanethiol solution, foamingwas noted in the flask. Stirring was continued at 20° C. for 1 ½ h andthe starting materialR(−)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol (12.5mmols=3.46 g) was added as a solid over 5 min. The reaction mixture washeated up slowly to 150° C. over 30 min. and stirred at this temperaturefor another hour. After this time the yellow brownish colored reactionmixture was rapidly cooled to 25° C. and quenched by adding it into aflask containing H₂O (90 mL). The mixture was charcoaled and filteredthrough celite. The mixture was washed with H₂O (1×25 mL) and 1N NaOH(1×50 mL). At this point the pH of the clear yellow colored solution was13. This was extracted with toluene (1×60 mL), followed by hexane (1×60mL). Under stirring at room temp it was neutralized to pH=9 with conc.HCl (3 mL). The resulting suspension was cooled at 5° C., stirred for 1h and the white solid was collected by filtration, dried in airovernight to give 2.6 g=79% of the phenol (mp:232-235° C.). Thiscompound (9.491 mmols=2.5 g) and fumaric acid (11.39 mmols=1.32 g) weredissolved in hot methanol/acetone (1:3) mixture (54 mL) and filteredleaving a clear light yellow colored solution. Under stirring at roomtemp H₂O (0.227 mL) was added to the solution. The solution becamecloudy immediately. Stirring was resumed for 2 h and the resulting whitesolid was collected by filtration, washed with acetone (2×50 mL), driedat 35° C. in a vacuum oven overnight to give 3 g=60% of analyticallypure compound.

EXAMPLE NO. 5S(+)-1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]cyclohexanol fumaratehydrate salt

[0024] a)S(+)-1-[2-(Dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol

[0025] To the mother liquor from the resolution after separation ofR(−)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol DT(−)Tsalt (see Example No. 2) was added H₂O (400 mL). The mixture has a pH=7.The pH was adjusted to 12 by adding 25% NaOH solution (150 mL). EtOAclayer was separated, washed with saturated NaCl solution (2×100 ml)dried (MgSO₄) and concentrated in vacuo to a volume of 100 mL. Hexane(400 mL) was added thereto and the whole was stirred at room temp for 1h, then at 0° C. for another 2 h. The white precipitate was collected byfiltration to give 37.5 g. This was dissolved in hot CH₂Cl₂ (110 mL).Charcoal (2 g) was added to the hot solution and stirred for 5 minutes.After filtration through solka floc, hexane (380 mL) was added to thefiltrate. The mixture was concentrated at atmospheric pressure to avolume of 250 mL and allowed to stay at room temp overnight. Theresulting white precipitate was collected by filtration to provide 29.7g. Recrystallization from CH₂Cl₂/Hexane (72/249 mL) gave analyticallypure S(+)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-cyclohexanol,25.4 g=25.4% yield. Rotation: +28.82° (in ethanol.). Anal. Calcd.: C,73.60; H, 9.81; N, 5.05. Found: C, 73.70; H, 10.10; N, 4.85.

[0026] b)S(+)-1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]cyclohexanol fumaratehydrate salt

[0027] To a stirred solution ofS(+)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-cyclohexanol (13.87g=50 mmols) in CH₂Cl₂ (500 mL), cooled to −40° C. under nitrogen wasadded slowly BBr₃ (10 mL=105.5 mmols) over a period of 15 min. Thereaction mixture warmed to 0° C. where it was stirred for 3 h. Duringthis time a gummy precipitate formed. Still at 0° C., 2.5 N NaOH (200mL) was added slowly over 1 h. Then the mixture was allowed to warm toroom temp and stirred overnight. CH₂Cl₂ was removed under vacuo leavingan aqueous layer having a pH=13-14. Aqueous layer was extracted withEtOAc (3×100 mL) and its pH dropped to 9. Combined EtOAc extracts werewashed with saturated NaCl solution, dried (MgSO₄), filtered andevaporated in vacuo to afford crude phenol (3.9 g=29.6%) as a whitesolid. Crude phenol (3.9 g=14.8 mmols) and fumaric acid (2.06 g=17.77mmols) were dissolved in a mixture of methanol/acetone (1:3) (81 mL) andstirred at room temp for 15 min. H₂O (0.325 mL=18 mmol) was added to theclear light yellow solution. Precipitation was noted immediately. Thewhole was stirred at room temp for 3 h. The resulting white precipitatewas collected by filtration, washed with acetone (1×35 mL) and dried togive 2.4 g (40.8%) of product. Recrystallization from MeOH/Acetone/H₂O(14 mL/46 mL/0.325 mL) gave 2.1 g=35% of analytically pureS(+)-4-[2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol fumaratehydrate salt. Rotation: −6.56° (in methanol) for the fumarate hydrate.+9.07° (in methanol) for the free base. Anal. Calcd: C, 60.43; H, 7.86;N, 3.52. Found: C, 60.47; H, 7.51; N, 3.32.

EXAMPLE NO. 6S(+)-4-[2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol fumaratehydrate salt

[0028] Under gentle N₂ stream 60% NaH (35 mmols=1.4 g) was washed withhexane, collected by filtration and transferred into a 250 mL 3 neckflask. DMF (20 mL) was added into the flask to cover the sodium hydrideand the suspension cooled to 10° C. Under stirring a solution ofethanthiol (32.40 mols=2.075 g=2.47 mL) in DMF (5 mL) was added dropwiseover 40 min. During the addition of the ethanthiol solution, foaming wasnoted in flask. Stirring was continued at 20° C. for 1 ½ h and thestarting materialS(+)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-cyclohexanol (12.5mmols=3.46 g) was added as a solid over 5 min. The reaction mixture washeated up slowly to 150° C. over 30 min and stirred at this temperaturefor another hour. After this time the yellow brownish colored reactionmixture was rapidly cooled to 25° C. and quenched by adding it into aflask containing H₂O (90 mL). The mixture was charcoaled and filteredthrough celite. The cake was washed with H₂O (1×25 mL) and 1N NaOH (1×50mL). At this point the pH of the clear yellow colored solution was 13.This was extracted with toluene (1×60 mL), followed by hexane (1×60 mL).Under stirring at room temperature it was neutralized to pH=9 with conc.HCl (3 mL). The resulting suspension was cooled at 5° C., stirred for 1h and the white solid was collected by filtration, dried in airovernight to give 2.4 g=72% of the phenol (mp 230-232° C.). Thiscompound (8.35 mmols=2.2 g) and fumaric acid (10.023 mmols=1.163 g) weredissolved in hot methanol/acetone (1:3) mixture (48 mL) and filteredleaving a clear light yellow colored solution. Under stirring at roomtemperature H₂O (0.2 mL) was added to the solution. The solution becamecloudy immediately. Stirring was resumed for 2 h and the resulting whitesolid was collected by filtration, washed with acetone (2×50 mL) anddried at 35° C. in a vacuum oven overnight to give 2.4 g of analyticallypure compound.

[0029] Tests were conducted to examine the effects of these compounds at5-HT2 receptor sites and on monamine uptake.

Methods

[0030] Male Sprague-Dawley rats (180-260 g, Charles River) were used inall neurochemical assays. Rats were housed in temperature-controlledquarters on a 12 hr light/12 hr dark cycle with free access to food andwater.

[0031] Neurotransmitter Uptake Inhibition

[0032] Uptake experiments were performed using a crude synaptosomalpreparation made from the brain tissue of adult male Sprague-Dawleyrats. The cortex of 1 rat for NE and 5-HT uptake was removed on ice andhomogenized in 20 volumes of 0.32 M sucrose/g tissue weight using aPotter-Elvehjem teflon homogenizer (3 strokes at 840 rpm). Thehomogenate was then centrifuged for 12 minutes at 1,000×g at 0-4° C. Theresulting supernatant was decanted into a chilled glass beaker and kepton ice until assayed. Protein concentration was determined by the methodof Lowry et al. (1).

[0033] For these experiments, all compounds were run in duplicate inconcentrations of 0.003-30.0 μM. Each tube received buffer (790 μl indrug tubes, 800 μl in control tubes), 10 μl of drug or standard (0.1 μMDMI for NE uptake and 3.0 μM zimelidine HCl for 5-HT uptake), 100 μlisotope (0.1 μM ³H-NE and 0.05 μM ¹⁴C-5-HT), and 100 μl tissue. Tubeswere incubated at 37° C. for 6 minutes. Incubation was terminated by theaddition of 2.5 ml buffer followed by vacuum filtration using a Brandelfiltration manifold with Whatman GF/B glass fiber filters and a secondwash with 2.5 ml buffer. Filters were added to 10 ml Hydrofluor, shakenfor 15 minutes and counted in a Packard 460CD scintillation counterequipped with dual-label dpm data reduction. Results were expressed aspmol uptake/mg protein/min. IC₅₀'s for uptake inhibition were calculatedby linear regression of logit [% of active uptake] vs. log[concentration of test drug].

[0034] Results

[0035] O-Desmethyl venlafaxine,4-[1-(2-dimethylamino)-2-(1-hydroxycyclohexyl)-ethyl]-phenol, and itsS(+) and R(−) enantiomers were tested for their ability to inhibit NEand 5-HT neurotransmitter uptake. O-Desmethyl venlafaxine inhibited 5-HTuptake (IC₅₀s=0.20 μM). Both enantiomers of O-Desmethyl venlafaxine wereactive in inhibiting 5-HT uptake with the (−) enantiomer being the morepotent [(+)O-Desmethyl venlafaxine IC₅₀=0.12 μM; (−)O-Desmethylvenlafaxine=0.06 μM]. Venlafaxine and O-Desmethyl venlafaxine alsoinhibited NE uptake (IC₅₀=0.72 μM and 75% inhibition at 0.3 μM,respectively). Both enantiomers of O-Desmethyl venlafaxine alsoinhibited NE uptake [(+)O-Desmethyl venlafaxine IC₅₀=0.72 μM; (−)O-Desmethyl venlafaxine IC₅₀=0.27 μM]. The (−) enantiomer of O-Desmethylvenlafaxine was more potent in inhibiting NE uptake.

[0036] Pharmaceutical compositions and formulations containing theenantiomers described herein can be produced in the same fashion andcontaining the same dosages as those described in the art forvenlafaxine hydrochloride. The pharmaceutical formulations orcompositions of this invention include those having as an activeingredient the R(−) enantiomer of O-Desmethyl venlafaxine substantiallyfree of S(+) O-Desmethyl venlafaxine. This invention also includesformulations in which an active ingredient is the S(+) enantiomer ofO-Desmethyl venlafaxine substantially free of R(−) O-Desmethylvenlafaxine. Each of these formulations also comprises one or morepharmaceutically useful excipients, carriers or adjuvants.

[0037] Formulations of the present invention may be produced using the Sor R enantiomer of O-Desmethyl venlafaxine, or a pharmaceuticallyacceptable salt or salt hydrate thereof, in the same fashion asdescribed for venlafaxine formulations in U.S. Pat. No. 5,530,013(Husbands et al.) and U.S. Pat. No. 5,506,270 (Upton et al.), both ofwhich are incorporated herein by reference.

[0038] Preferred oral extended release formulations of this inventionare comprised of the active enantiomer in admixture withmicrocrystalline cellulose and hydroxypropylmethylcellulose. Formed asbeads or spheroids, the drug containing formulation is coated with amixture of ethyl cellulose and hydroxypropylmethyl cellulose to providethe desired level of coating, generally from about two to about twelvepercent on a weight/weight basis of final product or more preferablyfrom about five to about ten percent (w/w), with best results obtainedat from about 6 to about 8 percent (w/w). More specifically, theextended release spheroid formulations of this invention comprise fromabout 30 to 40 percent R(−) O-desmethyl venlafaxine, from about 50 toabout 70 percent microcrystalline cellulose, NF, from about 0.25 toabout 1 percent hydroxypropylmethylcellulose, USP, and from about 5 toabout 10 percent film coating, all on a weight/weight basis. Andpreferably, the spheroid formulations contain about 35 percent activeingredient, about 55 to 60 percent microcrystalline cellulose NF(Avicel® PH101), about one half percent hydroxypropyl methylcellulose2208 USP (K3, Dow, which has a viscosity of 3 cps for 2% aqueoussolutions, a methoxy content of 19-24% and a hydroxypropoxy content of4-13%), and from about 6 to 8 percent film coating.

[0039] The film coating is comprised of 80 to 90 percent of ethylcellulose, NF and 10 to 20 percent hydroxypropyl methylcellulose (2910),USP on a weight/weight basis. Preferably the ethyl cellulose has aethoxy content of 44.0-51% and a viscosity of 50 cps for a 5% aqueoussolution and the hydroxypropylmethylcellulose is USP 2910 having aviscosity of 6 cps at 2% aqueous solution with a methoxy content of28-30% and a hydroxypropoxy content of 7-12%. The ethyl cellulose usedherein is Aqualon HG 2834.

[0040] Other equivalents of the hydroxypropylmethylcelluloses 2208 and2910 USP and ethyl cellulose, NF, having the same chemical and physicalcharacteristics as the proprietary products named above may besubstituted in the formulation without changing the inventive concept.Important characteristics of suitable hydroxypropylmethylcellulosesinclude a low viscosity, preferably less than 10 cps and more preferably2-5 cps, and a gel temperature above that of the temperature of theextrudate during extrusion. As explained below, these and othercharacteristics which enable the extrudate to remain moist and soft(pliable) are preferred for the hydroxypropylmethylcellulose. In theexamples below, the extrudate temperature was generally 50-55° C.

[0041] Specific examples of extended release compositions of thisinvention include the following.

FORMULATION EXAMPLE 1

[0042] A mixture of 44.8 parts (88.4% free base) of O-desmethylvenlafaxine or a salt or hydrate thereof, such as the fumarate hydratesalt, 74.6 parts of the microcrystalline cellulose, NF, and 0.60 partsof hydroxypropylmethyl cellulose 2208, USP, can be blended with theaddition of 41.0 parts water. The plastic mass of material is thenextruded, spheronized and dried to provide uncoated drug containingspheroids.

[0043] Stir 38.25 parts of ethyl cellulose, NF, HG2834 and 6.75 parts ofhydroxypropyl methylcellulose 2910, USP in a 1:1 v/v mixture ofmethylene chloride and anhydrous methanol until solution of the filmcoating material is complete.

[0044] To a fluidized bed of the uncoated spheroids apply 0.667 parts ofcoating solution per part of uncoated spheroids to obtain extendedrelease, film coated spheroids having a coating level of 3%.

[0045] The spheroids can then be sieved to retain the coated spheroidsof a particle size between 0.85 mm to 1.76 mm diameter. These selectedfilm coated spheroids are filled into hard gelatin capsulesconventionally.

FORMULATION EXAMPLE 2

[0046] Same as for Example 1 except that 1.11 parts of the film coatingsolution per part of uncoated spheroids is applied to obtain a coatinglevel of 5%.

FORMULATION EXAMPLE 3

[0047] Same as for Example 1 except that 1.33 parts of the film coatingsolution is applied to 1 part of uncoated spheroids to obtain a coatinglevel of 6%.

FORMULATION EXAMPLE 4

[0048] Same as for Example 1 except that 1.55 parts of the film coatingsolution is applied to 1 part of uncoated spheroids to obtain a coatinglevel of 7%.

[0049] One preferred extended release formulation of this inventioncomprises those of the active ingredient in spheroids comprised ofmicrocrystalline cellulose and, optionally, hydroxypropylmethylcellulosecoated with a mixture of ethyl cellulose and hydroxypropyl methylcellulose. Preferably, the spheroids are comprised of about 30% to 40%O-desmethyl venlafaxine hydrochloride by weight, about 50% to about 70%microcrystalline cellulose, NF, by weight, and from about 0.25% to about1% by weight of hydroxypropylmethylcellulose, USP, and coated with fromabout 2% to about 12% of total weight of film coating comprised of fromabout 80% to about 90% by weight of film coating of ethyl cellulose, NF,and from about 10% to about 20% by weight of film coating ofhydroxypropylmethylcellulose, USP.

[0050] A specific extended release formulation according to theparagraph above is wherein the spheroids are composed of about 37% byweight of the O-desmethyl venlafaxine enantiomer, about 0.5% by weightof hydroxypropylmethylcellulose 2208, and about 62% by weight ofmicrocrystalline cellulose. Another set of preferred compositions ofthis type are those wherein the film coating is comprised of ethylcellulose (4.81% of total weight) and hydroxypropylmethylcellulose(0.85% of total weight). In another such composition the film coatingcomprises 6-8% by weight of total weight, such as a film coatingcomprised of ethyl cellulose (2.48% of total weight) andhydroxypropylmethylcellulose (0.437% of total weight).

[0051] Yet another composition according to this invention are thosewherein the film coating composition is comprised of ethyl cellulosehaving a 44.0-51.0% content of ethoxy groups andhydroxypropylmethylcellulose having a methoxy content of 28.0-30.0% anda hydroxypropoxy group content of 7.0-12.0%. Film coating compositionsof this type may be comprised of about 85% by total weight of filmcoating of ethyl cellulose having a 44.0-51.0% content of ethoxy groups,and about 15% by total weight of film coating ofhydroxypropylmethylcellulose having a methoxy content of 28.0-30.0% anda hydroxypropoxy group content of 7.0-12.0%. A more specific filmcoating composition of this sort is comprised of 85% by weight of ethylcellulose type HG 2834 and 15% by weight of hydroxypropylmethylcellulosetype 2910.

[0052] Another extended release formulation for once dailyadministration of this invention comprises the O-desmethyl venlafaxineenantiomer, or a salt or hydrate thereof, which comprises spheroidscontaining 37.3% O-desmethyl venlafaxine enantiomer, 62.17%microcrystalline cellulose and 0.5% hydroxypropylmethylcellulose type2208, coated with a quantity of a mixture comprised of 85% ethylcellulose type HG 2834 and 15% hydroxypropyl-methylcellulose type 2910sufficient to give coated spheroids having a dissolution profile whichgives the desired release rate over a 24 hour period.

[0053] A further extended release formulation of this invention ismanufactured such that the spheroids are comprised of about 6% to 40%active compound by weight, about 50% to about 940% microcrystallinecellulose, NF, by weight, and, optionally, from about 0.25% to about 1%by weight of hydroxypropylmethylcellulose, USP, and coated with fromabout 2% to about 12% of total weight of film coating comprised of fromabout 80% to about 90% by weight of film coating of ethyl cellulose, NF,and from about 10% to about 20% by weight of film coating ofhydroxypropylmethylcellulose, USP. A preferred subset of these extendedrelease formulations are those wherein the spheroids are composed ofabout 8.25% by weight of active compound, or a pharmaceuticallyacceptable salt or hydrate thereof, and about 91.75% by weight ofmicrocrystalline cellulose, with a coating of from 3 to 5% by weight ofthe total weight. Another preferred subset or group are thoseformulations wherein the spheroids are composed of about 16.5% by weightof active drug agent and about 83.5% by weight of microcrystallinecellulose, with a coating of from 4 to 6% by weight of the total weight.

[0054] In other pharmaceutical compositions and formulations of thisinvention, the active ingredient comprises venlafaxine hydrochloridecombined with the O-desmethyl enantiomer, with the non-activeingredients being those described herein or in other formulations forvenlafaxine hydrochloride known in the art.

[0055] Uses of these extended release formulations may be described as amethod for providing a therapeutic blood plasma concentration of activedrug compound(s) over a 24 hour period with diminished incidences ofnausea and emesis which comprises administering orally to a patient inneed thereof, an encapsulated, extended release formulation thatprovides a peak blood plasma level of active agent in from about four toabout eight hours, said formulation containing O-Desmethyl venlafaxine,or a salt or salt hydrate thereof, as the active ingredient. The methodsare also useful for eliminating the troughs and peaks of drugconcentration in a patients blood plasma attending the therapeuticmetabolism of plural daily doses of active ingredient(s) which comprisesadministering orally to a patient in need thereof, an encapsulated,extended release formulation that provides a peak blood plasma level ofthe active agent in from about four to about eight hours, saidformulation containing O-Desmethyl venlafaxine, or a salt or salthydrate thereof, as the active ingredient.

What is claimed:
 1. A composition of matter comprisingR(−)-4-[2-(Dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol, or apharmaceutically acceptable salt or salt hydrate thereof, substantiallyfree of S(+)-4-[2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol,or a pharmaceutically acceptable salt or salt hydrate thereof.
 2. Acomposition of matter comprisingS(+)-4-[2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol, or apharmaceutically acceptable salt or salt hydrate thereof, substantiallyfree of R(−)-4-[2-(Dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol, ora pharmaceutically acceptable salt or salt hydrate thereof.
 3. Apharmaceutical composition comprising one or more pharmaceuticallyacceptable carriers and a pharmaceutically effective amount ofR(−)-4-[2-(Dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol, or apharmaceutically acceptable salt or salt hydrate thereof, substantiallyfree of S(+)-4-[2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol,or a pharmaceutically acceptable salt or salt hydrate thereof.
 4. Apharmaceutical composition comprising one or more pharmaceuticallyacceptable carriers and a pharmaceutically effective amount ofS(+)-4-[2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol, or apharmaceutically acceptable salt or salt hydrate thereof, substantiallyfree of R(−)-4-[2-(Dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol, ora pharmaceutically acceptable salt or salt hydrate thereof.
 5. A methodof treatment of depression in a mammal, the method comprisingadministering to a mammal in need thereof a pharmaceutically effectiveamount of R(−)-4-[2-(Dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol,or a pharmaceutically acceptable salt or salt hydrate thereof,substantially free ofS(+)-4-[2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol, or apharmaceutically acceptable salt or salt hydrate thereof.
 6. A method oftreatment of depression in a mammal, the method comprising administeringto a mammal in need thereof a pharmaceutically effective amount ofS(+)-4-[2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol, or apharmaceutically acceptable salt or salt hydrate thereof, substantiallyfree of R(−)-4-[2-(Dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol, ora pharmaceutically acceptable salt or salt hydrate thereof.